Migraine is a heritable, common, and severely debilitating neurological disorder, roughly 3-4 times more prevalent among women than men and its clinical presentation is remarkably diverse even when it can be clearly distinguished from other types of headaches, e.g. tension-type headache. The primary migraine heterogeneity is a dichotomy according to presence (MA) or absence (MO) of aura, typically a visual disturbance preceding the migraine attack. Heterogeneity is also manifest in a diversity of clinical features accompanying the migraine attack, including nausea, photophobia, phonophobia, pulsatile pain character, unilateral pain, attack duration, etc. The different presentations may be related to underlying differences in pathophysiology that may also contribute to migraine comorbidities, such as ischemic stroke and coronary heart disease with MA, and both restless legs syndrome and cervical artery dissection with MA or MO. Meanwhile, recent genetic analysis has identified 12 single nucleotide polymorphisms (SNPs) for association with migraine in the population and still unpublished work raises the total number of migraine SNPs to ~40. We recently reported (PLoS Genetics [2014] doi: 10.1371/journal.pgen.1004366) that some of the original 12 genetic associations appear to be selective for migraine sub-classified according to status of aura or the clinical features of the migraine attack. These findings suggest that migraine sub-classification may be more complex than the dichotomy of MA v. MO, and that genetic analysis of migraine sub-classes and their comorbidities may help characterize the underlying pathophysiology of migraine. In Specific Aim 1 of the proposed research, we will use conventional and novel latent class modeling techniques applied to aura status and the clinical features of the migraine headache to evaluate the evidence for subclasses of migraine other than MA v. MO in the adult population. We will then assess evidence for selective associations between the 40 SNPs and conventional or latent sub-classes, and how genetic information from the SNPs may modify the latent sub-classes definitions to provide clues to their underlying pathophysiology. In Specific Aim 2, we will use newly available heritability estimation methods to investigate the overlap of genetic contribution between MA v. MO, between the latent sub-classes of migraine from Specific Aim 1, and between migraine sub-classes and the comorbidities of migraine. These analyses will partition heritability according regions of the genome with annotated biological function, e.g. biological pathways, cell-type-specific active chromatin, or sex-specific gene expression to provide further insights into underlying migraine biology. Analysis would be performed initially in the Women's Genome Health Study, our cohort that was used for discovery of the first robustly replicating, genome-wide significant migraine loci in the population. Replication and follow-up analysis would be performed in a richly collaborative setting. Through the proposed analysis, we hope to improve understanding some of migraine's heterogeneity with implications for diagnosis and therapeutic approaches.